Project Summary/Abstract Examining the Heterogeneity of Fibroblasts in the Pancreatic Microenvironment Pancreatic cancer has a highly dysplastic tumor stroma present from the onset of carcinogenesis. The cellular components of this stroma consist largely of activated fibroblasts and infiltrating immune cells. Since pancreatic cancer is largely refractory to chemotherapy, the current ideology is to target the stroma in conjunction with the cancer in order to enhance drug perfusion and effectiveness. The utility of targeting the fibroblasts within the stroma remains controversial though-- data show the fibroblasts support tumor growth while also restraining it from being as aggressive. The fibroblasts in the pancreatic cancer microenvironment have long been treated like a homogenous population, derived from the pancreatic stellate cells; however, no lineage tracing experiment has demonstrated this possibility. Recent studies have indicated that the fibroblast population is not uniform, raising the possibility that different subpopulations might either promote or restrain cancer progression and growth. Characterizing the diverse fibroblast populations within the pancreatic cancer stroma is necessary to target this population therapeutically. A pilot study in collaboration with Dr. Deneen Wellik, co-Sponsor for this application, discovered a population of fibroblasts in the adult pancreas that express Hoxb6 and that includes pancreatic stellate cells. Importantly, Hoxb6 is not widely expressed in fibroblast populations in other organs and tissues. Based on this observation, we are in the position to lineage trace and functionally evaluate normal pancreas fibroblasts during pancreatic carcinogenesis. The overall objective of this proposal is to identify and functionally characterize the Hoxb6 fibroblast subset in the context of pancreatic cancer. The HYPOTHESIS of this application is that the Hoxb6 fibroblast population gives rise to an active component of the fibrotic stroma that affects cancer growth. Transgenic reporter mouse models and primary cell cultures will be used to characterize and functionally assess this novel population of fibroblasts. =